The present invention provides methods of enhancing the antibody dependent cellular cytotoxicity (xe2x80x9cADCCxe2x80x9d) effect of anti-IgE to treat IgE-associated disorders.
Allergic diseases, including allergic asthma and allergic rhinitis, are characterized by an IgE-mediated early phase response, which occurs within seconds to minutes of allergen exposure, and a late phase response, which is cell-mediated and occurs 4 to 24 hours later. Allergic asthma and allergic rhinitis are characterized by infiltration of eosinophils into the site of allergen exposure. Specifically, during the early phase of the allergic response, activation of Th2-type lymphocytes stimulates the production of antigen-specific IgE antibodies, which are bound by mast-cell and basophil receptors (e.g., Fc xcex5 RI) and which, upon binding an allergen and being cross-linked, in turn trigger the release of histamine and other mediators of inflammation from mast cells and basophils. During the late phase response, IL-4 and IL-5 production by CD4 Th2 cells is elevated. These cytokines appear to play a significant role in recruiting eosinophils into the site of allergen exposure, where tissue damage and lung dysfunction result.
Currently, the standard therapy for many allergic diseases is by desensitization to the allergens. This desensitization involves exposure by injection, over several months, to the allergen, with the expectation that anti-allergen IgG antibodies will be endogenously generated. This therapy has mixed results in patients, and is not effective for many. There is also a risk of anaphylaxis.
A new therapy for treatment of allergic diseases is pending approval by the U.S. FDA and other regulatory agencies. Anti-IgE monoclonal antibodies, which do not bind to IgE bound to the Fc xcex5 RI on basophils or mast cells, can reduce the amount of circulating IgE and provide effective treatment for allergic asthma and allergic rhinitis. See U.S. Pat. Nos. 5,53,144 and 5,614,611. These anti-IgE antibodies may be inducing some level of ADCC and helping to eliminate IgE-producing B cells, which would aid in longer-term suppression of IgE. ADCC is known to be induced by the human Ig isotypes IgG1 and IgG3, as well as by the mouse IgG2a Fc region. Enhancement of ADCC may, therefore, help eliminate IgE-producing B cells and further improve the efficacy of anti-IgE.
Antibody-dependent cellular cytotoxicity or ADCC is the result of Natural Killer (NK) cells recognizing and eliminating a target cell, such as a virally infected cell, coated with IgG antibodies via their Fc xcex3 RIII (CD16). The Fc receptor of the NK cell binds to the IgG on the surface of the target cell and mediates ADCC. Macrophages also act as killer cells through ADCC. Specific IgG and IgE molecules enhance the macrophagesxe2x80x9d ability to kill schistosomules (Roitt, et al., In: Immunology, 5th ed. Mosby, p. 246 (1998)) U.S. Pat. No. 5,500,362 discusses a chimeric IgG monoclonal antibody 2H7, which binds to B-cells and appears to mediate ADCC against lymphoma cells. They suggest its possible usefulness in developing immunoconjugates to deliver drugs, toxins, etc. to tumor cells.
The ADCC events involved in IgE-associated disorders may be enhanced with an immune stimulating nucleotide sequence, including a CpG-containing oligonucleotide, as described in U.S. Pat. No. 6,239,116, as well as related CpG-containing oligonucleotides, and certain related oligonucleotides (hereinafter collectively referred to as xe2x80x9cISOsxe2x80x9d). Bacterial CpG-DNA is a potent Th1-like adjuvant triggering a strong Th1 biased antibody response, and concomitantly suppressing the Th2 response (Davis, H. L. et al., J. Immunol. 1 60:870-876 (1998)). CpG-DNA is also a potent single B-cell mitogen, which is capable of driving more than 95% of Binto an activated state (Krieg, A. M. et al., Nature 374:546-549 (1995)). These innate immune responses can be mimicked by synthesized unmethylated CpG-containing oligodeoxynucleotides (CpG-ODNs). Bactivated by bacterial CpG sequences or CpG-ODNs show increased expression of surface class-II major histocompatibility complex (MHC) molecules and the co-stimulatory molecules B7-1 and B7-2 (Krieg, A. M., In: Delivery Strategies for Antisense Oligonucleotide Therapeutics, Ed. Akhtar, S., CRC Press, Inc., pp 177-190; Davis, H. L. et al., J. Immunol. 160: 870-876 (1998)). This suggests the possibility that the CpG xe2x80x9cmotif,xe2x80x9d composed of CG dinucleotides, may directly enhance the antigen-presenting function of B-cells. Although the effects of the CpG motif on Tare less clear, highly purified Tthat are stimulated through the T-cell receptor show synergistic proliferative responses to CpGs, indicating a mechanism through which CpGs could promote antigen-specific Tresponses (Bendigs, S. et al., Eur. J. Immunol. 29:1209-1218 (1999)).
CpG-ODNs strongly stimulate NK lytic activity and IFN-xcex3 production (Tokunaga, T et al., J. Natl. Cancer Institute 72:955-962 (1984); Yamamoto S., J. Immunol. 148:4072-4076 (1992)). Antigen-presenting cells, such as monocytes and dendritic cells, are activated by CpG-ODNs resulting in the production of Th1 cytokines jakob, T et al., J. Immunol. 161:3042-3049 (1998)), as well as MHC-class II molecules and co-stimulatory B7-1 and B7-2 molecules (Stacy, K. J. et al., J. Immunol. 1 57:2116-2122 (1996); Sparwasser, T. et al., Eur. J. Immunol. 28:2045-2054 (1998)).
CpG-ODNs are, therefore, potent inducers and stimulators of a wide range of antigen-dependent and antigen-independent immune responses. Since CpGactivate NK cells, they are useful for enhancing the antibody dependent cellular cytotoxicity (ADCC) of anti-tumor antibodies. CpGcan shift the Tresponse from a Th2-type response to a Th1-type response, which can result in down-modulating of the allergic responses (Kline, J. N. et al., J. Immunol. 160:2555-2559 (1998); Sur, S. et al., J. Immunol. 162:5575-5582 (1999); Shirota, H. et al., J. Immunol. 164:5575-5582 (2000); Jahn-Schmid, B. et al., J. Allergy Clin. Immunol. 104:1015-1023 (1999); Broide, D. H. et al., J. Clin. Immunol. 21:175-182 (2001)). Thus, a longer-lasting therapeutic effect in treating IgE-mediated allergic diseases may be achieved by combining desensitization therapy with anti-IgE therapy and an ISO, than with desensitization therapy alone.